
Cyclopeptides are polypeptides in which the terminal amine and carboxyl groups form an internal peptide bond. Several cyclopeptides are known for their advantageous medicinal properties. An excellent example of this is the class of echinocandins which are potent antifungals. Cyclopeptides can be naturally occurring compounds but may also be obtained by total synthesis or by synthetic or genetic modification of naturally occurring or naturally produced precursors; the latter class is referred to as semi synthetic cyclopeptides. Examples of medicinally useful echinocandins are the cyclohexapeptides anidulafungin, caspofungin, cilofungin and micafungin which are useful in treating fungal infections especially those caused by Aspergillus, Blastomyces, Candida, Coccidioides and Histoplasma. 
Caspofungin (1-[(4R,5S)-5-[(2-aminoethyl)amino]-N2-(10,12-dimethyl-1-oxotetradecyl)-4-hydroxy-L-ornithine]-5-[(3R)-3-hydroxy-L-ornithine]-pneumocandin B0; (1) with R1=—NH(CH2)2NH2, R2=—C(O)(CH2)8CH(CH3)CH2CH(CH3)CH2CH3, R3=—H, R4=—(CH2)2NH2, R5=—H) is a semi synthetic cyclohexapeptide derivable from naturally occurring echinocandins such as for instance echinocandin B, pneumocandin A0 or pneumocandin B0.
Although nature can provide a substantive part of the complex chemical structure of semi synthetic cyclohexapeptides, and in many cases having all chiral centers in the required configuration, a major disadvantage nevertheless is that during fermentation often side products are formed that carry through the process and eventually end up as impurities. Only in few cases can fermentation processes be tuned in such a way as to prevent formation of impurities. Particularly when these impurities are structurally closely related to the main product, their removal is usually tedious and often requires unprecedented purification approaches as the main products in question are chemically unstable and/or prone to racemization.
The preparation of caspofungin (1) from fermentatively obtained pneumocandin B0 is a process wherein removal of impurities is an important issue. A multitude of structurally related impurities occurring during fermentation of pneumocandin B0 has been described. Examples are compounds having an additional methyl function (such as pneumocandin A0, pneumocandin A1, pneumocandin A2, pneumocandin A3, pneumocandin A4, pneumocandin A5, pneumocandin A6), compounds lacking one or two hydroxyl groups (such as pneumocandin B1, pneumocandin B2, pneumocandin B5, pneumocandin B6, pneumocandin E0), compounds having a 4-hydroxy proline rather than a 3-hydroxy proline moiety (pneumocandin C0), compounds having additional hydroxyl groups (such as pneumocandin D0, pneumocandin D2) or the recently described impurity A (US 2009/0324635) wherein, in the caspofungin structure, one of the hydroxy-L-ornithine moieties is replaced by an L-serine moiety.
Recently, in WO 2012/117038 a process was disclosed for preparing azacyclohexapeptide salts using chromatography and crystallization. Although the method is suitable for the laboratory scale preparation of caspofungin of high purity, there remains a need for alternative methods that are industrially applicable, i.e. on larger scale using equipment more appropriate and that yield a product with (more) favorable morphology.